Alcohol and intestinal microvascular endothelium-immune axis and the role of gut derived immune nutrients

酒精与肠道微血管内皮-免疫轴以及肠道源性免疫营养素的作用

基本信息

批准号：
10248366
负责人：
Gail Ann Cresci
金额：
$ 52.02万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10248366
关键词：
Acetates Acute Adolescent Adult Affect Alcohol consumption Alcohol-Induced Disorders Alcohols Animal Model Autoimmune Diseases Biological Blood Circulation Blood Vessels Brain Butyrates Cells Chronic Coculture Techniques Colon Development Diffuse Endothelial Cells Endothelium Endotoxins Epithelial Ethanol Fermentation Functional disorder Gene Expression Regulation Goals Healthcare Heavy Drinking Hepatic Homeostasis Homing Human Immune Immune response Immune system Immunity Impairment Inflammation Inflammatory Response Intercellular Junctions Interleukin-10 Intestinal permeability Intestines Laboratories Lamina Propria Leukocytes Link Lipopolysaccharides Liver Lung Malignant Neoplasms Mediating Microbe Microvascular Permeability Morbidity - disease rate Mucositis Mucous Membrane Mus Myocardium Nutrient Oral Organ Oxidative Stress Pancreas Pathology Perfusion Play Population Portal vein structure Prevention Prodrugs Productivity Propionates Proteins Regulation Regulatory T-Lymphocyte Reporting Role STAT3 gene Splenocyte Supplementation System T cell response T-Cell Homing Receptors T-Lymphocyte TLR4 gene Testing Therapeutic Therapeutic Agents Tight Junctions Tretinoin United States Virus Diseases Volatile Fatty Acids alcohol effect alcohol exposure alcohol testing alcohol use disorder cost cytokine driving force feeding gastrointestinal epithelium gut dysbiosis gut microbiome immune activation immune function improved in vivo insight intestinal epithelium intestinal homeostasis intestinal injury liver inflammation liver injury macromolecule macrophage microbial mortality mouse model novel novel therapeutics nutrient metabolism organ growth organ injury pathogenic bacteria preservation prevent preventable death protective effect recruit response transcription factor transcriptome sequencing tributyrin

项目摘要

ABSTRACT Chronic ethanol exposure is associated with gut dysbiosis, impaired immunity, and the development of organ dysfunction leading to a rising appreciation for inter-organ crosstalk for ethanol-induced pathologies. First hit by ethanol ingestion, the intestine and gut microbiome play a central role in immune system homeostasis. Chronic ethanol decreases gut bacterial abundance and diversity and destabilizes the intestinal epithelial barrier, which is associated with reduced luminal butyrate and intestinal all-trans retinoic acid (atRA) levels, systemic endotoxin, and inflammation. Intestinal microvascular endothelial cells (EC), located within the intestinal lamina propria, are critical for mucosal immune function by recruiting and activating leukocytes and regulating gut vascular perfusion. Following ethanol-induced epithelial barrier disruption and endotoxin translocation, proinflammatory molecules interact with intestinal microvascular EC and immune cells within the lamina propria. Endothelial and immune cell activation by bacterial endotoxins leads to their dysfunction. The intestinal microvascular endothelial barrier serves as second defensive barrier for a disrupted epithelium, providing additional protection against macromolecule and microbe translocation. Butyrate and atRA are intestinal-generated immune nutrients known to promote epithelial barrier function, and immune homeostasis via T-lymphocyte regulation. We have shown butyrate (tributyrin) supplementation mitigates ethanol-induced gut-liver injury by preventing disassembly of epithelial tight junction proteins, reducing oxidative stress, and promoting expression of intestinal microvascular endothelial associated junctional proteins and immune cells in mouse proximal colon. Here we propose the hypothesis that through ethanol’s disruption of the gut microbiome, depletion of butyrate and all-trans retinoic acid, and subsequent destabilization of the intestinal epithelial barrier and translocation of endotoxin, intestinal microvascular endothelium become functionally disrupted and activated which induces intestinal T-cell dysregulation and inflammation. We will test two specific aims. Aim 1: Test the hypothesis that ethanol-induced gut dysbiosis, resultant butyrate depletion and epithelial barrier destabilization disrupts intestinal microvascular endothelial junctional protein integrity. Using both in vivo and ex vivo approaches, we will study how butyrate mitigates the effects of ethanol on endothelium disassembly of barrier junctional proteins. Aim 2: Test the hypothesis that ethanol activates and induces alterations in T-cell homing and Treg expansion within the intestinal lamina propria which causes intestinal microvascular endothelial dysregulation in a butyrate and atRA dependent manner. We will utilize ex vivo co-culture system, and in vivo wild-type and Foxp3DTR mice to test for ethanol-induced activation of intestinal microvascular EC, T-cell homing receptors, and Treg expansion and cytokine responses in lamina propria and splenocytes. Importantly, intestinal microvascular EC has not been studied in the context of ethanol, butyrate and atRA, and therefore new mechanistic insights may bring novel therapeutics to protect against ethanol’s disruption in intestinal homeostasis.

抽象的慢性乙醇暴露与肠道营养不良，免疫受损和器官发展有关功能障碍导致对乙醇诱导的病理学间串扰的兴趣不断上升。首先打乙醇摄入，肠和肠道微生物组在免疫系统稳态中起着核心作用。慢性的乙醇减少了肠道细菌的丰度和多样性，并破坏了肠上皮屏障的稳定性，该屏障与减少的河丁酸和肠道全反式视黄酸（ATRA）水平相关，全身内毒素，和炎症。肠道微血管内皮细胞（EC），位于肠道椎板内，通过募集和激活白细胞和控制肠道血管灌注来对粘膜免疫功能至关重要。乙醇引起的上皮屏障破坏和内毒素易位，促炎分子与椎板层中的肠道微血管EC和免疫球相互作用。内皮和免疫电池细菌内毒素的细胞激活导致其功能障碍。肠微血管内皮屏障作为破坏上皮的第二次防御障碍，提供了额外的保护大分子和微生物易位。丁酸酯和ATRA是已知的肠道产生的免疫营养素我们已证明可以通过T淋巴细胞调节促进上皮屏障功能和免疫稳态。丁酸酯（Tributyrin）补充可通过防止拆卸来减轻乙醇诱导的肠肝损伤上皮紧密连接蛋白，减少氧化应激，并促进肠道微血管的表达小鼠近端结肠中内皮相关的连接蛋白和免疫细胞。在这里我们提出假设通过乙醇的破坏肠道微生物组，丁酸酯和全反式视网膜的部署酸，随后的肠上皮屏障和内毒素的易位微血管内皮在功能上被破坏和激活，从而诱导肠道T细胞失调和炎症。我们将测试两个具体目标。目标1：检验乙醇诱导的假设肠道营养不良，导致的丁酸酯部署和上皮屏障破坏肠道微血管内皮连接蛋白完整性。使用体内和体内方法，我们将研究如何丁酸酯减轻乙醇对屏障联合蛋白内皮拆卸的影响。目标2：测试假设乙醇激活并影响T细胞归巢和Treg扩展的变化肠道椎板的肠道层，导致丁酸酯和抗肌酸中肠道微血管内皮失调依赖方式。我们将利用体内共培养系统，体内野生型和Foxp3dtr小鼠进行测试乙醇诱导的肠道微血管EC，T细胞归巢受体和Treg膨胀的激活以及椎板和脾细胞中的细胞因子反应。重要的是，肠道微血管EC尚未在乙醇，丁酸酯和ATRA的背景下进行研究，因此新的机械见解可能会带来新颖预防乙醇在肠道稳态中的破坏的治疗剂。